MEDIATORS OF ACCELERATED GRAFT ARTERIOSCLEROSIS

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Arteriosclerosis of graft vessels is the most common long-term cause of death of a patient with a transplanted heart. Graft arteriosclerosis is a diffuse, circumferential disease, characterized by an infiltrate of inflammatory cells, and a neointima formed by smooth muscle cells. A wide variety of soluble mediators affect the migration and proliferation of these cells into graft vessels, and we propose that two mediators, nitric oxide and transforming growth factor-beta, are crucial to the development of graft arteriosclerosis. Our preliminary data show that immediately after cardiac transplantation, humans produce a burst of nitric oxide and other radicals. Furthermore, our data show that in the months after transplantation, nitric oxide synthase is expressed in mononuclear inflammatory cells migrating into arteries of cardiac allografts in rats and humans. Nitric oxide can have both beneficial and harmful effects to the host, but the role of nitric oxide in the vessel wall is unknown. Our first specific aim is to determine the pattern of expression of inducible nitric oxide synthase. and determine the effect of nitric oxide on the vessel wall. If synthesized in cardiac allografts, transforming growth factor-beta could in theory damage endothelial cells, and also cause smooth muscle cell proliferation by inducing the release of platelet derived growth factor. Our preliminary data show that the effects of these growth factors can be abrogated by the over-expression of dominant negative mutant receptors in vitro. Our second specific aim is to determine the role of transforming growth factor-beta and platelet derived growth factor in the development of graft arteriosclerosis, using a unique method to study isolated, modified endothelial cells in vivo. We then plan in our third specific aim to examine how transforming growth factor-beta affects the production of nitric oxide in endothelial cells. These aims are directly related to other projects within this program project. Transforming growth factor-beta induces endothelial cell apoptosis, which is studied in Project 1. Regulation of nitric oxide production in dysfunctional endothelial cells is also explored in Project 1. CMV, studied in Project 2, can induce nitric oxide synthase in infected cells. Fixation of complement, studied in Project 4, can also induce production of nitric oxide. Both nitric oxide and transforming growth factor-beta are released by activated macrophages, which are involved in antigen presentation during cell-mediated immunity studied in Project 5. Thus, many pathways could lead to the release of the mediators we are studying, which in turn lead to the development of graft arteriosclerosis.